The Risk of Keratinocyte Cancer in Patients With Vitiligo

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In this interview, Dr Rosalie M. Luiten discusses her study’s discovery of a lower risk of nonmelanoma, or keratinocyte, skin cancer, in patients with vitiligo, including the potential non-immune-mediated and immune-mediated mechanisms that may be responsible for this finding. 

The Dermatologist: How does the incidence of keratinocyte cancer (KC) in patients with vitiligo compare with the general population, and what are the potential implications of this finding? 

Dr Luiten: Patients with vitiligo have 2 times less risk of developing KC than the general population. We do not have exact numbers for the general population because they are not in most of the registries, but from epidemiologic studies, we know that the relative risk of KC is about 0.5. The implication is that although patients with vitiligo are always a bit afraid of having an elevated risk of getting skin cancer because they lack pigmentation, this fear is not necessary. Of course, patients with vitiligo should take appropriate sun protection measures, as we all should. 

The Dermatologist: What potential mechanisms might explain the reduced risk of KC in patients with vitiligo, considering the expected increased risk due to the absence of skin pigmentation? 

Dr Luiten: Skin pigmentation, which is, of course, a protection against the sun, is lacking in vitiligo, so you would indeed expect more skin cancer. But pigmentation is not the only thing that protects against skin cancer. We formulated several hypotheses, both non-immune-mediated and immune-mediated. 

A non-immune-mediated finding might be that there is more of the tumor suppressor protein P53 in the skin of patients with vitiligo. P53 has a role in apoptosis, DNA repair, and senescence of cells. It is a key regulator of what happens to cells, whether they die, stop growing, or are at risk for being transformed in a malignant fashion. To have more of this regulator would mean that you have more of an alarm system of preventing malignant cells to occur and grow out as a tumor. P53 has not only been found to be increased in vitiligo lesions, but also in the non-lesional skin. 

An immune-mediated finding may be that the immune activation levels are higher in vitiligo, not just against the melanocytes but in a general sense. This means there may be more immune protection in general, which might contribute to less skin cancer risk in patients with vitiligo. It could be that immune response regulation does not function well in patients with vitiligo, which means they get too much immune activation. But on the other hand, this lack of immune regulation might also result in having a more immune active state, protecting against skin cancer in that way. This immune activation might also take place mostly in the skin. Less immune regulation, more immune activation, and adaptive immunity (T cells and natural killer cells are also increased in vitiligo) together could create an environment that is quite alert to malignant cells and then as they appear, they might be suppressed immediately. 

The Dermatologist: Could cross-reactivity of melanocyte-specific CD8+ T cells in patients with vitiligo contribute to a reduced risk of KC development and, if so, how? 

Dr Luiten: This is also a hypothesis we formulated. What we know about the immune response to vitiligo is that it is highly specific toward melanocytes, the pigment cells in the skin. But on the other side, it could be that these T cells do show some cross reactivity, so the recognized antigens may also be recognized on a KC cell. There could be some crossbreed activity on the stem cell level between melanocytes and there may be some shared antigens between melanocytes and KC cells. An example of this being possible is in psoriasis, another highly inflammatory skin disease. There has been a study in which they found T cells in psoriasis skin that were recognizing melanocytes. This is an interesting finding that even though T cells have a highly specific receptor against a specific antigen, there could also be some molecular similarity allowing cross reactivity. 

The Dermatologist: How do microRNAs contribute to the lower risk of KC in patients with vitiligo, and how might their dysregulation in vitiligo skin affect oncogenic transcription factors? 

Dr Luiten: Studying microRNAs is a relatively new field in vitiligo research. MicroRNAs are important regulators, and there were 2 RNAs found that affect oncogenic transcription factors associated with KC. The interesting part is that they also compared the microRNA profile in vitiligo and KC, and they found that one excludes the other on the microRNA level. This is still a basic finding, but it does show there are processes that are suppressive for KC in vitiligo. 

The Dermatologist: How might environmental factors like UV exposure and oxidative stress interact with genetic and immunologic factors to influence KC risk in patients with vitiligo? 

Dr Luiten: There are a diversity of factors involved in vitiligo that positively or negatively contribute in some way to cancer risk. Of course, we know UV is a risk factor for skin cancer, but UV also increases the oxidative stress levels in the skin, which might then increase the P53 levels that are more suppressive. Then if you look at the genetic factors, most of them are immune related; only a minority of the genes are pigmentation related. For example, there are genes associated with immune surveillance. Decreased immune regulation is also found on a genetic level, for example, the CTLA-4 gene. All these factors have a role, and they point in the direction that vitiligo might have protective characteristics against KC. 

The Dermatologist: How might insights into immune mechanisms contribute to the development of targeted therapies for both vitiligo and KC? 

Dr Luiten: These findings could have implications for phototherapy for vitiligo. There is always a concern about cancer risk with UVB phototherapy, and this might be a little bit less relevant for patients with vitiligo knowing that they have a decreased risk. It also indicates that if we understand more of vitiligo’s pathogenesis, we could also find new ways for therapy because a better understanding leads to more therapeutic targets being identified in the long run. 

KCs are not the cancers that we have the most knowledge about when it comes to immune responses. Melanoma is the front-runner in cancer immunology. We know a lot about anti-tumor immunity against melanoma, but we know less about anti-tumor immunity against KC. These findings could also serve as a proof of concept that there is a potential for immune-mediated suppression of KC, making KC more suitable for immunotherapy, which is being developed for many cancers and now being considered for KC. 

Reference 

Rooker A, Ouwerkerk W, Bekkenk MW, Luiten RM, Bakker WJ. The risk of keratinocyte cancer in vitiligo and the potential mechanisms involved. J Invest Dermatol. 2024;144(2):234-242. doi: 10.1016/j.jid.2023.08.012